In a focal model of brain ischemia in the spontaneously hypertensive rat, microvascular perfusion, accumulation of inflammatory mediators, and indices of cellular injury have been correlated spatially and temporally by means of multiple label immunohistochemistry in order to study their role in acute stroke. The findings clearly demonstrate that progressive impairment of microcirculation occurs in regions of brain that undergo progressive damage in the early hours of ischemia. Depletion of leukocytes with the anti-leukocyte antibody, RP-3, and inhibition of tumor necrosis factor-alpha (TNF-alpha) with TNF-binding protein reduce postischemic brain injury. In a mouse model of focal ischemia, prior exposure to TNF-alpha has been shown to induce ischemic tolerance. Oral tolerance to myelin basic protein has been shown to reduce brain injury after focal ischemia in the Lewis rat, implicating immune and inflammatory mechanisms in stroke.